The research proposed in this application will investigate the overall hypotheses that matrix metalloprotease (MMP) activity has a critical role in the migration of T cells that leads to immunity to influenza virus, but that aberrant responses after high dose or highly virulent infections could make T cell-derived MMPs a factor in pathology. Influenza viruses cause significant annual illness and death with recurrent seasonal epidemics and sporadic devastating pandemics. The efficiency of highly pathogenic influenza viruses has been attributed to potent and aberrant inflammatory responses, which can result in severe immunopathological damage and death in humans, as found with the H5N1 virus. T cells can contribute to pulmonary damage by direct lysis of infected cells and the production of pro-inflammatory cytokines. Migration of T cells into the site of inflammation and their effector responses in situ are crucial steps towards immunity, but could also contribute to the high morbidity and mortality associated with pathogenic strains. We hypothesize that the ability of T cells to efficiently cross the lung endothelial barrier and move through the basement membrane, which is essential for their function, is regulated by MMPs. MMPs have the proteolytic capability to mediate cleavage of the collagen network that makes up the basement membrane. T cells can express MMPs and dysregulation of these molecules could have far-reaching consequences. Although, MMP activity has been implicated in a variety of pulmonary diseases, nothing is yet known regarding the function of MMPs in regulating the in vivo T cell response to influenza viruses. In this application we will investigate whether MMP activity in T cells accounts for their migration across the basement membrane of the lung in response to influenza virus and as such enables the development of T cell-mediated pathology. We will investigate the relative contribution of MMP expression in different T cell subpopulations to their function using adoptive transfers of T cells that lack MMP activity by genetic deficiency (MMP2 and MMP9 knock-out) or by inhibition (knock-down by retroviral transduction). In addition we will identify the factors that induce MMP expression in vivo. We will focus on the LFA/ICAM interaction, which regulates CD4/CD8 T cell migration in the lung and the effects of extrinsic cytokine production, since it is associated with pathology. Both can elicit MMP activity in T cells ex vivo. The discovery of new insights into the role(s) of MMP in T cell function during influenza virus pathogenesis could elucidate the balance between immunity and pathology and may therefore have considerable therapeutic relevance. PUBLIC HEALTH RELEVANCE Influenza viruses cause significant annual illness and death with recurrent seasonal epidemics and sporadic devastating pandemics. The goal of the proposed research is to investigate the responses that underlie the development of immunopathology during influenza virus infection. These studies will provide new insights into the regulation of immunity to influenza viruses and might offer a strategy to treat clinical symptoms.